ACTIV-5 / Big Effect Trial (BET-C) for the Treatment of COVID-19

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Completed

CT.gov ID

NCT04988035

Collaborator

(none)

176

Enrollment

Locations

Arms

9.1

Actual Duration (Months)

4.5

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a platform trial to conduct a series of randomized, double-blind, placebo-controlled trials using common assessments and endpoints in hospitalized adults diagnosed with COVID-19. BET is a proof-of-concept study with the intent of identifying promising treatments to enter a more definitive study. The study will be conducted in up to 70 domestic sites and 5 international sites. The study will compare different investigational therapeutic agents to a common control arm and determine which have relatively large effects. In order to maintain the double blind, each intervention will have a matched placebo. However, the control arm will be shared between interventions and may include participants receiving the matched placebo for a different intervention.

The goal is not to determine clear statistical significance for an intervention, but rather to determine which products have clinical data suggestive of efficacy and should be moved quickly into larger studies. Estimates produced from BET will provide an improved basis for designing the larger trial, in terms of sample size and endpoint selection. Products with little indication of efficacy will be dropped on the basis of interim evaluations. In addition, some interventions may be discontinued on the basis of interim futility or efficacy analyses.

One or more interventions may be started at any time. The number of interventions enrolling are programmatic decisions and will be based on the number of sites and the pace of enrollment. At the time of enrollment, subjects will be randomized to receive any one of the active arms they are eligible for or placebo. Approximately 200 (100 treatment and 100 shared placebo) subjects will be assigned to each arm entering the platform and a given site will generally have no more than 3 interventions at once.

The BET-C stage will evaluate the combination of remdesivir with danicopan vs remdesivir with a placebo. Subjects will be assessed daily while hospitalized. Once subjects are discharged from the hospital, they will have a study visit at Days 8, 15, 22, 29, and 60 as an outpatient. The Day 8, Day 22 and Day 60 visits do not have laboratory tests or collection of samples and may be conducted by phone. All subjects will undergo a series of efficacy and safety laboratory assessments. Safety laboratory tests and blood (serum, plasma and RNA) research samples on Day 1 (prior to study product administration) and Days 3, 5, 8, and 11 while hospitalized. Blood research samples plus safety laboratory tests will be collected on Day 15 and 29 if the subject attends an in-person visit or is still hospitalized. However, if infection control considerations or other restrictions prevent the subject from returning to the clinic, Day 15 and 29 visits may be conducted by phone and only clinical data will be obtained.

The primary objective is to evaluate the clinical efficacy of danicopan relative to the control arm in adults hospitalized with COVID-19 according to clinical status (8-point ordinal scale) at Day 8.

Condition or Disease	Intervention/Treatment	Phase
COVID-19	Drug: Danicopan Other: Placebo Drug: Remdesivir	Phase 2

Detailed Description

The primary objective is to evaluate the clinical efficacy of danicopan relative to the control arm in adults hospitalized with COVID-19 according to clinical status (8-point ordinal scale) at Day 8. The key secondary objectives are 1) to evaluate the clinical efficacy of danicopan as assessed by time to recovery compared to the control arm 2) to evaluate the proportion of subjects alive and without respiratory failure through Day 29.

Contacts:

20-0013 Central Contact

Telephone: 1 (301) 7617948

Email: DMIDClinicalTrials@niaid.nih.gov

Study Design

Study Type:

Interventional

Actual Enrollment :

176 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

A Multicenter Platform Trial of Putative Therapeutics for the Treatment of COVID-19 in Hospitalized Adults

Actual Study Start Date :

Jul 21, 2021

Actual Primary Completion Date :

Apr 23, 2022

Actual Study Completion Date :

Apr 23, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Remdesivir + Danicopan (< 70 years) For participants < 70 years, 200 mg intravenous (IV) loading dose of Remdesivir on Day 1, followed by a 100 mg once-daily IV maintenance dose up to a 10-day total course while hospitalized, and 400 mg oral (PO) (or via nasogastric [NG] or gastrostomy [G] tube) loading dose danicopan, followed by 250 mg 4 times daily (QID) for the duration of the hospitalization up to a 14-day total course. End of danicopan treatment tapered as 250 mg 3 times daily (TID) for 2 days, followed by 250 mg twice daily (BID) for 2 days, until complete cessation (total treatment duration up to 18 days or 4 days after discharge). Total danicopan participants, N=100.	Drug: Danicopan Danicopan is a small molecule, orally administered complement factor D (FD) inhibitor Drug: Remdesivir Remdesivir is a single diastereomer monophosphoramidate prodrug for the intracellular delivery of a modified adenine nucleoside analog GS-441524.
Experimental: Remdesivir + Danicopan (>/= 70 years) For participants >/= 70 years, 200 mg intravenous (IV) loading dose of Remdesivir on Day 1, followed by a 100 mg once-daily IV maintenance dose up to a 10-day total course while hospitalized, and 300 mg oral (PO) (or via nasogastric [NG] or gastrostomy [G] tube) loading dose danicopan, followed by 200 mg 4 times daily (QID) for the duration of the hospitalization up to a 14-day total course. End of danicopan treatment tapered as 200 mg 3 times daily (TID) for 2 days, followed by 200 mg twice daily (BID) for 2 days, until complete cessation (total treatment duration up to 18 days or 4 days after discharge). Total danicopan participants, N=100.	Drug: Danicopan Danicopan is a small molecule, orally administered complement factor D (FD) inhibitor Drug: Remdesivir Remdesivir is a single diastereomer monophosphoramidate prodrug for the intracellular delivery of a modified adenine nucleoside analog GS-441524.
Active Comparator: Remdesivir + Placebo (< 70 years) For participants < 70 years, 200 mg intravenous (IV) loading dose of Remdesivir on Day 1, followed by a 100 mg once-daily IV maintenance dose up to a 10-day total course while hospitalized, and 400 mg oral (PO) (or via nasogastric [NG] or gastrostomy [G] tube) loading dose danicopan matching placebo, followed by 250 mg 4 times daily (QID) for the duration of the hospitalization up to a 14-day total course. End of danicopan matching placebo treatment tapered as 250 mg 3 times daily (TID) for 2 days, followed by 250 mg twice daily (BID) for 2 days, until complete cessation (total treatment duration up to 18 days or 4 days after discharge). Total danicopan matching placebo participants, N=100.	Other: Placebo Danicopan matching placebo tablet Drug: Remdesivir Remdesivir is a single diastereomer monophosphoramidate prodrug for the intracellular delivery of a modified adenine nucleoside analog GS-441524.
Active Comparator: Remdesivir + Placebo (>/= 70 years) For participants >/= 70 years, 200 mg intravenous (IV) loading dose of Remdesivir on Day 1, followed by a 100 mg once-daily IV maintenance dose up to a 10-day total course while hospitalized and 300 mg oral (PO) (or via nasogastric [NG] or gastrostomy [G] tube) of loading dose danicopan matching placebo followed by 200 mg 4 times daily (QID) for the duration of the hospitalization up to a 14-day total course. End of danicopan matching placebo treatment tapered as 200 mg 3 times daily (TID) for 2 days, followed by 200 mg twice daily (BID) for 2 days, until complete cessation (total treatment duration up to 18 days or 4 days after discharge). Total danicopan matching placebo participants, N=100.	Other: Placebo Danicopan matching placebo tablet Drug: Remdesivir Remdesivir is a single diastereomer monophosphoramidate prodrug for the intracellular delivery of a modified adenine nucleoside analog GS-441524.

Outcome Measures

Primary Outcome Measures

Clinical status on an 8-point ordinal scale. [Day 8]
Clinical status assessed using ordinal scale: 1) Not hospitalized, no new or increased limitations on activities; 2) Not hospitalized, but new or increased limitation on activities and/or requiring new or increased home oxygen, continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP); 3) Hospitalized, not requiring new or increased supplemental oxygen - no longer requires ongoing medical care; 4) Hospitalized, not requiring new or increased supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 5) Hospitalized, requiring new or increased supplemental oxygen; 6) Hospitalized, requiring new or increased non-invasive ventilation or high-flow oxygen devices; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 8. Death.

Secondary Outcome Measures

Change from baseline of inflammation and coagulation markers [Day 1 through Day 29]
Markers include C-reactive protein (CRP), ferritin, D-dimer, fibrinogen, and lactate dehydrogenase (LDH).
Change in alanine aminotransferase (ALT) over time [Day 1 through Day 29]
Change in aspartate transaminase (AST) over time [Day 1 through Day29]
Change in creatinine over time [Day 1 through Day 29]
Change in hemoglobin over time [Day 1 through Day 29]
Change in international normalized ratio (INR) [Day 1 through Day 29]
Change in platelets over time [Day 1 through Day 29]
Change in total bilirubin over time [Day 1 through Day 29]
Change in white blood cell (WBC) count with differential over time [Day 1 through Day 29]
WBC with differential, hemoglobin, platelets, creatinine, total bilirubin, alanine aminotransferase (ALT), aspartate transaminase (AST), and international normalized ratio (INR).
Clinical Status on an 8-point ordinal scale [Day 15 through Day 29]
Secondary Clinical Status on an 8-point ordinal scale Clinical status assessed using ordinal scale: 1) Not hospitalized, no new or increased limitations on activities; 2) Not hospitalized, but new or increased limitation on activities and/or requiring new or increased home oxygen, continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP); 3) Hospitalized, not requiring new or increased supplemental oxygen - no longer requires ongoing medical care; 4) Hospitalized, not requiring new or increased supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 5) Hospitalized, requiring new or increased supplemental oxygen; 6) Hospitalized, requiring new or increased non-invasive ventilation or high-flow oxygen devices; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 8. Death. Day 15 through Day 29 No
Cumulative incidence of Grade 3 and 4 clinical and/or laboratory adverse events [Day 1 through Day 60]
Cumulative incidence of serious adverse events (SAE) [Day 1 through Day 60]
Discontinuation or temporary suspension of study product administration [Day 1 through Day 29]
For any reason
Duration of hospitalization [Day 1 through Day 29]
Measured in days.
Duration of Intensive Care Unit stay [Day 1 through Day 29]
Measured in days.
Duration of mechanical ventilation or extracorporeal membrane oxygenation (ECMO) use [Day 1 through Day 29]
Measured in days.
Duration of new mechanical ventilation or extracorporeal membrane oxygenation (ECMO) use [Day 1 through Day 29]
Measured in days.
Duration of new non-invasive ventilation/high-flow oxygen use [Day 1 through Day 29]
Measured in days.
Duration of non-invasive ventilation/high-flow oxygen use [Day 1 through Day 29]
Measured in days.
Duration of supplemental oxygen use [Day 1 through Day 29]
Measured in days.
Incidence of new mechanical ventilation or extracorporeal membrane oxygenation (ECMO) use [Day 1 through Day 29]
Measured in days.
Incidence of new non-invasive ventilation/high-flow oxygen use [Day 1 through Day 29]
Measured in days.
Mean change in the ordinal scale [Day 1 through Day 29]
Clinical status assessed using ordinal scale: 1) Not hospitalized, no new or increased limitations on activities; 2) Not hospitalized, but new or increased limitation on activities and/or requiring new or increased home oxygen, continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP); 3) Hospitalized, not requiring new or increased supplemental oxygen - no longer requires ongoing medical care; 4) Hospitalized, not requiring new or increased supplemental oxygen but requiring ongoing medical care (COVID-19 related or otherwise); 5) Hospitalized, requiring new or increased supplemental oxygen; 6) Hospitalized, requiring new or increased non-invasive ventilation or high flow oxygen devices; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 8) Death.
Subject mortality [Day 1 through Day 60]
Date and cause of death (if applicable)
The proportion of subjects with a baseline score of 5 or 6 who are alive and without respiratory failure [Day 1 through Day 29]
Subjects in ordinal scale 5 or 6 at baseline who did not meet either of the following two categories at any point through Day 29: 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 8) Death.
The proportion of subjects with any baseline score who are alive and without respiratory failure [Day 29]
Proportion of subjects who did not meet either of the following two categories on Day 29: 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 8) Death.
Time to an improvement of one category using an ordinal scale. [Day 1 through Day 29]
Clinical status assessed using ordinal scale: 1) Not hospitalized, no new or increased limitations on activities; 2) Not hospitalized, but new or increased limitation on activities and/or requiring new or increased home oxygen, continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP); 3) Hospitalized, not requiring new or increased supplemental oxygen - no longer requires ongoing medical care; 4) Hospitalized, not requiring new or increased supplemental oxygen but requiring ongoing medical care (COVID-19 related or otherwise); 5) Hospitalized, requiring new or increased supplemental oxygen; 6) Hospitalized, requiring new or increased non-invasive ventilation or high flow oxygen devices; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 8) Death.
Time to an improvement of two categories using an ordinal scale. [Day 1 through Day 29]
Clinical status assessed using ordinal scale: 1) Not hospitalized, no new or increased limitations on activities; 2) Not hospitalized, but new or increased limitation on activities and/or requiring new or increased home oxygen, continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP); 3) Hospitalized, not requiring new or increased supplemental oxygen - no longer requires ongoing medical care; 4) Hospitalized, not requiring new or increased supplemental oxygen but requiring ongoing medical care (COVID-19 related or otherwise); 5) Hospitalized, requiring new or increased supplemental oxygen; 6) Hospitalized, requiring new or increased non-invasive ventilation or high flow oxygen devices; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 8) Death.
Time to death [Day 1 through Day 29]
Time to recovery [Day 1 through Day 29]
Day of recovery is defined as the first day on which the subject satisfies 1 of the following 3 categories from the ordinal scale (and does not return to a score of 4 or higher for the remainder of the study period): 1) Not hospitalized, no new or increased limitations on activities; 2) Not hospitalized, but new or increased limitation on activities and/or requiring new or increased home oxygen, continuous positive airway pressure (CPAP), or bilevel positive airway pressure (BiPAP); 3) Hospitalized, not requiring new or increased supplemental oxygen - no longer requires ongoing medical care.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 99 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Admitted to a hospital with symptoms suggestive of COVID-19 and requires ongoing medical care.
Subject (or legally authorized representative) provides informed consent prior to initiation of any study procedures.
Subject (or legally authorized representative) understands and agrees to comply with planned study procedures.
Male or non-pregnant female adult >/=18 years of age at time of enrollment.
Illness of any duration and has laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain reaction (PCR) or other commercial or public health assay (e.g., Nucleic Acid Amplification Test [NAAT], antigen test) in any respiratory specimen or saliva </=14 days prior to randomization.
Illness of any duration, and requiring, just prior to randomization, supplemental oxygen (any flow), mechanical ventilation or extracorporeal membrane oxygenation (ECMO) (ordinal scale category 5, 6, or 7).*

*If written documentation of the positive test result is not available at the time of enrollment (e.g., report came from other institution), the test should be repeated and the subject may be enrolled if positive.

Women of childbearing potential and men must agree to either abstinence or use at least one acceptable method of contraception** from the time of screening through 30 days after the last dose of danicopan for women and 90 days after the last dose for men.

**Acceptable methods include barrier contraceptives (condoms or diaphragm) with spermicide, intrauterine devices (IUDs), hormonal contraceptives, oral contraceptive pills, and surgical sterilization.

Agrees not to participate in another blinded clinical trial (both pharmacologic and other types of interventions) for the treatment of COVID-19 through Day 29

Exclusion Criteria:

aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 times the upper limit of normal.
Subjects with a low glomerular filtration rate (eGFR), specifically:
Subjects with an eGFR 15-30 mL/min are excluded unless in the opinion of the principal investigator (PI), the potential benefit of participation outweighs the potential risk of study participation.
All subjects with an eGFR <15 mL/min (including hemodialysis and hemofiltration) are excluded.
Pregnancy or breast feeding
Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours of enrollment.
Allergy to any study medication.
Received five or more doses of remdesivir prior to screening.
Treatment with a complement inhibitor in the prior 8 weeks.*
Has active uncontrolled opportunistic infection, or uncontrolled cirrhosis.*
History of infection with N. meningitidis.*
Known history of hypersensitivity to danicopan or its excipients.*
Has a medical condition that could, in the judgment of the investigator, limit the interpretation and generalizability of trial results.
Positive test for influenza virus during the current illness (influenza testing is not required by protocol).
History of liver cirrhosis.*
Previous participation in an ACTIV-5/BET trial.
Refuses to refrain from breastfeeding from the time of screening through 30 days after the last dose of danicopan.*
Refuses to receive prophylactic antibiotics against meningococcal infections if the subject has not been vaccinated in the 3 years prior to Study Day 1.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham School of Medicine - Infectious Disease	Birmingham	Alabama	United States	35233
2	Kern Medical Center	Bakersfield	California	United States	93306-4018
3	UCSF Fresno Center for Medical Education and Research - Clinical Research Center	Fresno	California	United States	93721
4	University of California Los Angeles Medical Center - Westwood Clinic	Los Angeles	California	United States	90095
5	Hoag Hospital Newport Beach	Newport Beach	California	United States	92663
6	Penrose Hospital - Emergency Medicine	Colorado Springs	Colorado	United States	80907
7	St. Francis Medical Center	Colorado Springs	Colorado	United States	80923
8	St. Anthony Hospital	Lakewood	Colorado	United States	80228-1704
9	St. Anthony Hospital North Health Campus	Westminster	Colorado	United States	80023
10	Nuvance Health Danbury Hospital - Infectious Disease	Danbury	Connecticut	United States	06810
11	Yale School of Medicine - The Anlyan Center for Medical Research & Education - Immunobiology	New Haven	Connecticut	United States	06519-1612
12	Nuvance Health - Norwalk Hospital - Asthma Pulmonary and Critical Care Medicine	Norwalk	Connecticut	United States	06856
13	University of Florida Health - Shands Hospital - Division of Infectious Diseases and Global Medicine	Gainesville	Florida	United States	32610
14	Mayo Clinic Florida	Jacksonville	Florida	United States	32224
15	Great Lakes Clinical Trials	Chicago	Illinois	United States	60640
16	Carle Foundation Hospital	Urbana	Illinois	United States	61801
17	Northwestern Medicine - Central DuPage Hospital - Infectious Disease	Winfield	Illinois	United States	60190
18	Norton Healthcare	Louisville	Kentucky	United States	40202
19	University of Louisville - Division of Infectious Diseases	Louisville	Kentucky	United States	40202
20	Brigham and Women's Hospital - Infectious Diseases	Boston	Massachusetts	United States	02115-6110
21	William Beaumont Hospital - Royal Oak Campus - Infectious Disease	Royal Oak	Michigan	United States	48073
22	Hennepin Healthcare Research Institute	Minneapolis	Minnesota	United States	55415
23	Mayo Clinic, Rochester - Infectious Diseases	Rochester	Minnesota	United States	55905-0001
24	University of Nebraska Medical Center - Infectious Diseases	Omaha	Nebraska	United States	68105
25	Jacobi Medical Center	Bronx	New York	United States	10461-1119
26	Montefiore Medical Center - Infectious Diseases	Bronx	New York	United States	10467-2401
27	The State University of New York - University at Buffalo - Department of Medicine	Buffalo	New York	United States	14203
28	Mount Sinai School of Medicine - Medicine - Infectious Diseases	New York	New York	United States	10029-6504
29	Nuvance Health - Vassar Brothers Medical Center	Poughkeepsie	New York	United States	12601
30	Stony Brook Medicine - Stony Brook University Hospita	Stony Brook	New York	United States	11794
31	Wake Forest Baptist Health - Infectious Diseases	Winston-Salem	North Carolina	United States	27157
32	St. Charles Health System - St. Charles Bend Hospital	Bend	Oregon	United States	97701
33	Doylestown Hospital	Doylestown	Pennsylvania	United States	18901
34	Penn State Health Milton S. Hershey Medical Center - Division of Infectious Diseases	Hershey	Pennsylvania	United States	17033
35	Kent County Memorial Hospital	Warwick	Rhode Island	United States	02886
36	Hendrick Health - Hendrick Medical Center	Abilene	Texas	United States	79601
37	Baylor Scott & White Health - Baylor University Medical Center - North Texas Infectious Disease Consultants	Dallas	Texas	United States	75246
38	University of Utah - Infectious Diseases	Salt Lake City	Utah	United States	84132
39	West Virginia University - Infectious Diseases Clinic	Morgantown	West Virginia	United States	26506